It is well known in the art that pyridazinone compounds have an inhibitory effect on platelet aggregation, and the racemic modifications of the pyridazinone compound of the present invention are disclosed in WO 94/09784 corresponding to U.S. Pat. No. 5,663,172.
The said racemic modification has significant inhibitory effect on platelet aggregation, and the side effect caused thereby has been improved to an extent.
However, there is still such problems in the racemic modification that said racemic modifications is not enough chemically stable because of the noncrystalline state and further due to the influence generated from the remaining solvent and water therein, and therefore, the quality of the racemic modification have significantly varied in the industrial scale production. Therefore, it is an object of the present invention to provide optically active pyridazinone derivative which has an inhibitory effect on platelet aggregation, less side effect and higher physical stability.
The present invention is directed to a compound, (R)-(-)-4,5-dihydro-5-methyl-6-4-(2-propyl-3-oxo-1-cyclohexenyl)amino!ph enyl!-3(2H)-pyridazinone represented by the following general formula I!; ##STR1## the crystalline form thereof and methods for manufacturing the said compound and the crystalline form thereof.
The noncrystalline racemic modifications (.+-.)-(I)! of the compounds of the present invention can be manufactured according to the method disclosed in WO 94/09784, for example.
The crystalline optically active compound of the present invention, (R)-(-)-4,5-dihydro-5-methyl-6-4-(2-propyl-3-oxo-1-cyclohexenyl)amino!ph enyl!-3(2H)-pyridazinone, can be prepared by firstly obtaining the racemic modification of said compound either by means of optical resolution by using column chromatography for optical isomers separation or by using optically active raw material II! to thereby prepare said racemic modification, and subsequently conducting the crystallization of the racemic modification obtained in any of water, organic solvent or the admixture thereof according to a method generally known in the art, either after isolating the said optically active compound from the solvent or without such isolation. More specifically, the racemic modification can be prepared by taking a procedure, where firstly stirring the optically active compound in an solvent selected from a group consisting of water, hydrophilic organic solvent such as ethanol and the admixture thereof, at a temperature of from -20.degree. to 80.degree. C., more preferably from 0.degree. to 40.degree. C., then collecting the crystals precipitated, and finally drying said crystals according to a method generally-known in the art. In the procedure hereinabove, it is possible to hasten said crystallization by adding a piece of the crystals into the solvent as seed crystal. In case the admixture of water and an organic solvent is used for the solvent described above, it is preferable that the admixture contains water at a concentration of from 5 to 95%, and more preferably from 30 to 70%.
Whereas, in some cases, such crystalline optically active compound can be directly obtained from optical resolution by using column chromatography for optical isomers separation, however, it should be noted that such crystalline optically active compounds is naturally falling within the scope of the crystalline optically active compound of the present invention.
For the column chromatography for optical isomers separation, it is preferable to use CHIRALCEL OD, OJ, CHIRALPAK AD, AS (manufactured by Daicel Chemical industries, Ltd.) or SUMICHIRAL OA-25001 (manufactured by Sumika Chemical Analysis Service, Ltd.).
The manufacturing method of the crystalline optically active compound by using the optically active raw material (II) is shown as the following reaction formula. ##STR2##
The reaction is taken place in an inactive organic solvent, preferably in benzene, toluene, xylene, lower alcohols. DMF, DMSO or the like, in the presence of an acid catalyzer, such as hydrochloric acid, sulfuric acid, acetic acid, and p-toluenesulfonic acid, under applying heating to maintain temperature in a range of from room temperature to 200.degree. C. By removing water resulting in during the reaction by azeotropic distillation or the else, the reaction can be taken place more efficiently. The optical purity of the product can be increased by conducting the recrystallization of the product in any of ethyl acetate, chloroform, methanol, ethanol, and ethanol-water mixture. In particular, the objective product having high optical purity higher than 95% can be obtained by using a solvent mixture of benzene or toluene and DMSO or DMF, or the like, as a reaction solvent, and by using p-toluenesulfonic acid as an acid catalyzer at a concentration range of from 0.001 to 0.1 mole respective to 1 mol of the amino form.
(R)-6-(aminophenyl)-5-methylpyridazine-3(2H)-one II! can be manufactured according to a method generally known in the art. For example, the compound II! can be manufactured either from the racemic modification thereof by applying optical resolution according to the method described in WO 9212135 or the else, or from the optically active acid chloride thereof according to the following reaction formula. ##STR3##
(R)-(-)-4,5-dihydro-5-methyl-6-4-(2-propyl-3-oxo-1-cyclohexenyl) amino!phenyl!-3(2H)-pyridazinone according to the present invention or the pharmaceutically acceptable complex thereof can be administrated to human and animals by alone or together with commonly-used carriers for medical preparations. For the unit preparation form for administration, there is no particular limitation and any unit preparations can be selected appropriately depending upon the requirements. For examples of the unit preparations, oral use preparations, such as tablets, granules and solutions for oral administration, and parenteral use preparations, such as injections, are exemplified. There is no particular limitation in the dose of the active principle to be administrated, and therefore, the dose should be determined appropriately from the wide range basing on the route of administration, compound selected, and the objectives dosed, namely human or animals.
In the present invention, the oral use preparations, such as tablets, capsules and solution for oral administration, described above can be manufactured according to customary methods in the art. The tablets can be prepared by admixing the compound of the present invention or the pharmaceutically acceptable complex thereof with pharmaceutical fillers, such as starch, milk sugar, gelatin, magnesium stearate, talc and gum arabic. The capsules can be manufactured by admixing the compound of the present invention or the pharmaceutically acceptable complex thereof with inactive fillers or diluents for pharmaceutical use and then filling the admixture into hard gelatin capsules, soft capsules or the like. Also, medicated syrups and elixirs can be manufactured by admixing the compound of the present invention or the pharmaceutically acceptable complex thereof with sweetener such as sucrose, antiseptics, such as methyl- and propylparaben, coloring agents, seasoning agents, etc. Whereas, the parenteral use preparations can be manufactured according to customary methods in the art as well. Namely, the preparations for parenteral administration can be manufactured by dissolving the compound of the present invention or the pharmaceutically acceptable complex thereof in sterilized liquid carriers. For the liquid carrier, water and saline are preferably used. Liquid preparations having a desired transparency, stability and suitability for parenteral use can be manufactured by firstly dissolving approximately 1 to 500 mg of the active principle in polyethylene glycol, which is soluble in water and an organic solvent and having a molecular weight of from 200 to 5000. In such liquid preparations, any lubricants, such as polyvinyl pyrrolidone, polyvinyl alcohol, sodium carboxymethyl cellulose and methyl cellulose, are preferably contained. In addition, antibacterial and antimold agents, such as benzyl alcohol, phenol and thyromethal, may be contained in the liquid preparation described above. Furthermore, isotonic agents, such as sucrose and sodium chloride, local anesthetics, stabilizers, buffer, etc. may be contained in the liquid preparations, if appropriate. In case of the preparations for parenteral administration, the preparations can be frozen in order to improve the stability thereof after filling them into containers, and it is possible to remove water from the preparations by using lyophilization technique generally known in the art. The lyophilized preparations can be readily used by re-preparing the lyophilized power just before the use.